Acyl CoA: diacylglycerol acyltransferase (hereinafter referred to as “DGAT”) is an integral membrane enzyme that catalyses the last step of the glycerol 3-phosphate pathway, synthesizing triacylglycerol from the substrates sn-1,2-diacylglycerol and fatty acyl CoA. As a rule, the biosynthesis of triacylglycerol is accomplished through the glycerol 3-monophosphate pathway (the liver and adipose tissues) and the monoacylglycerol pathway (intestinal epithelial cells).
Recently, at the Gladstone Institute of Cardiovascular Diseases, U.S.A., DGAT-1 gene deficient mice have been used in the study of DGAT functions, yielding evidence that DGAT-1 deficient mice are protected from diet-induced obesity even when they are weaned on a high-fat diet, and that DGAT-1 deficiency enhances insulin and leptin deficiency, improving glucose metabolism. A subsequent research result showed that the selective inhibition of DGAT, an enzyme that catalyzes the biosynthesis of triglycerides in insulin-sensitive tissues, such as adipose tissues, skeletal muscles, the liver, beta cells of the pancreas, etc., is useful in the prevention and treatment of obesity and type II diabetes mellitus (Chen H C, et al., Trends Cardiovasc. Med., 10, 188-192, 2000; Farese Jr. et al., Curr. Opin. Lipidol., 11, 229-234, 2000; A. Subauste et. al., Currunt Drug Target-Immun, Endocrine & Metabol Disorders, 3, 263-270, 2003; Y. Yu et. al. Annals of Medicine, 36. 252-261).
Decreased activity of DGAT results in the blockage of enzymatic reactions for triglyceride biosynthesis or a reduction in biosynthesis yield. When the biosynthesis of triglyceride is restricted by inhibiting DGAT, an enzyme participating in the final step of triglyceride biosynthesis, there are a decrease in the accumulation of fats in adipose tissues, a decrease in the size of adipose cells, and an increase in energy expenditure attributable to increased ambulatory physical activity and increased expression of uncoupling proteins, thereby giving rise to resistance to diet-induced obesity (Smith S J. et al., Nature genetics, 25, 87-90, 2000; Chen et al., J Clin Invest., 109(8), 1049-1055, 2002; Chen et al., J Clin Invest., 111, 1715-1722, 2003; Chen et al. Am. J. Physiol. Endocronol. Metab., 284, E213-218, 2003).
In addition, it is known that the inhibition of DGAT restricts the accumulation of fats in non-adipose tissues, such as the skeletal muscles, the liver, the pancreas and the like, leading to an improvement in insulin resistance.
Insulin stimulation results in decreased serine inhibitory phosphorylation and tyrosine phosphorylation of IRS-(insulin receptor substance-1), and increased insulin signaling transduction through PI-3K (phosphatidylinositol-3 kinase), PKB (protein kinase B, Akt) and PKCλ (protein kinase Cλ), thereby increasing the number of the glucose transporter GLUT-4.
When the activity of DGAT within cells is decreased, the activities of PI-3K, PKB and PKCλ increase, thus stimulating GLUT-4 exocytosis and increasing the amount of glucose introduced into the cells. In other words, the inhibition of DGAT activity enhances insulin sensitivity (Chen et al., Arterioscler Thromb Vasc Biol. 25(3), 482-486, 2005; Chen et al., J Clin Invest. 111(11), 1715-22, 2003; Chen et al., J Clin Invest. 109(8), 1049-1055, 2002; Chen et al., Diabetes. 51(11), 3189-3195, 2002; Subauste and Burant., Curr Drug Targets Immune Endocr Metabol Disord. 3(4), 263-270, 2003). With the discovery of the correlation between the inhibition of DGAT and the subjugation of insulin resistance, DGAT arises as a therapeutic target for type II diabetes mellitus, which is characterized by the obstruction of glucose absorption due to insulin resistance, but with normal insulin secretion.
Synthetic chemicals known as DGAT inhibitors include biphenyl-4-yl-carbonylaminoacid derivatives (WO2006044775, Bayer Pharmaceuticals Corp), urea derivatives (WO2006019020, WO2006004200, Sankyo Co), pyrrolecarboxylic acid derivatives (JP05213985A, Mitsubishi Kasei Corp, Japan) and phosphonic acid ester derivatives (JP2004067635A, Otsuka Pharmaceut Factory Inc., Japan). DGAT inhibitors in the form of naturally occurring materials include polyacetylenes from Ginseng (Korean Patent No. 0460438, Lee et al. Planta Med. 70, 179-200, 2004), quinolone alkaloids, tanshinones, prenylflavonoids isolated from Evodia officinalis, Salvia miltiorrhiza BUNGE, and Sophora flavescens (Korean Pat. No. 0577320, Ko et al., Arch. Phar. Res. 25, 446-448, 2002, Korean Patent No. 0507989).
Also reported as DGAT inhibitors are roselipins (U.S. Pat. Nos. 6,432,682 (2002) and 6,608,185 (2003)) (Omura et al., the Kitasato Institute and Graduate School of Pharmaceutical Sciences), cochlioquinone A and A1 (J. Antibiot., 56, 967, 2003; J. Antibiot., 57, 59, 2004), amidepsines and xanthohumol. Other examples include eicosapentaenoic acid, 2-bromooctanoate and niacin (Rustan et al., J. Lipid. Res., 29, 1417-1426, 1988, Ganji et al. J. Lipid. Res., 45, 1835-1845).
Leading to the present invention, intensive and thorough research into active materials inhibitory of DGAT, conducted by the present inventors, resulted in the finding that indole derivatives inhibit the biosynthesis of triglycerides to bring about various effects including the prevention of diet-induced obesity, the amelioration of blood lipid levels, and the prevention of fat accumulation in adipose cells, and thus can be applied to the treatment of metabolic disorders, such as obesity, diabetes and the like.